朱亮《药学导论》3药动学-zhuliang.ppt
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1、药物代谢动力学 Pharmacokinetics,朱亮 上海交通大学医学院,Why do me need to know PK? - Optimize drug therapy to obtain a predictable response!,(1) Drug of choice (2) How much (3) How often (4) For how long,Definition,体内药物浓度随时间变化的动力学规律,PK discusses how a drug is: absorbed (taken into the body) distributed (moved into va
2、rious tissues) metabolized (changed into form that can be excreted) excreted (removed from the body),Drug Administration,Drug Concentration in Systemic Circulation,Drug in Tissues of Distribution,Drug Metabolism or Excreted,Drug Concentration at Site of Action,Pharmacologic Effect,Clinical Response,
3、Toxicity,Efficacy,Absorption,Distribution,Elimination,Pharmacokinetics,Pharmacodynamics,Drug must have necessary properties to be transported from its site of administration to its site of action. Drug should be inactivated or excreted from the body at a reasonable rate so its actions will be of app
4、ropriate duration.,Example: Penetration of Antimicrobial Agents into Anatomic Compartments,Levofloxacin achieves skin tissue/plasma peak concentration ratio of 1.4, epithelial lining fluid to plasma ratio of 2.8, and urine to plasma ratios of 67. The failure rate of therapy was 0% in patients with u
5、rinary tract infections, 3% in patients with pulmonary infections, and 16% in patients with skin and soft tissue infections,To be effective, each antibiotic has to get to where the pathogen is, to penetrate into the infected compartment,penicillin G, are actively transported out of the cerebrospinal
6、 fluid (CSF) and achieve CSF concentrations of only 0.5-5% of that achieved in plasma,Drug at action site,Metabolites,Excreted drug,Drug in body,用药后药物在体内量的变化曲线,% of dose,第 一 节 药物分子的跨膜转运,Drug Transport,一、药物通过细胞膜的方式:,水溶性小分子药物通过细胞膜的水通道 受流体静压或渗透压的影响 肠粘膜上皮细胞及其它大多数细胞膜孔道48, 仅水、尿素等小分子水溶性物质能通过, 分子量100者即不能通过
7、肾小球毛细血管内皮孔道约40,除蛋白质外,血浆中的溶质均能通过,滤过(Filtration)水溶性扩散,绝大多数药物采用此方式 扩散速度与脂溶性正相关 药物还需同时具有水溶性 受药物理化性质和pH影响 分子量小 脂溶性高 非解离型 极性小的 容易透过 存在离子障(ion trapping)现象,简单扩散脂溶性扩散,The non-ionized molecules usually are more lipid soluble and can diffuse readily across the cell membrane. In contrast, the ionized molecules
8、usually are less able to penetrate the lipid membrane because of their low lipid solubility, and passage will depend on the leakiness of the membrane related to the membranes electrical resistance.,Ka =, H+ A HA,pKa = pH - log, A HA, A HA,10 pH-pKa =,酸性药 :,碱性药:,pH和pKa决定药物分子解离多少,HendersonHasselbalch
9、equation,A + H+HA,HAH+ + A, A HA,10pH-pKa =,pH=7,pH=4,1,1,102,105,色甘酸钠 (Cromolyn Sodium):pKa = 2,= 107-2 = 105, A HA,10pH-pKa =,= 104-2 = 102,弱酸性药物 在酸性的环境中解离少,容易透过细胞膜 在碱性的环境中解离多,不容易透过细胞膜 弱碱性药物 在酸性的环境中解离多,不容易透过细胞膜 在碱性的环境中解离少,容易透过细胞膜,主动转运 (Active transport),逆浓度梯度,耗能 需要载体 载体对药物有选择性 饱和性 竞争性,易化扩散 (Facili
10、tated diffusion; Carrier-mediated diffusion) 如:Glucose, Iron, 5-fluorouracil, calcium, lead 需特异性载体 顺浓度梯度,不耗能,膜动转运(cytosis/pinocytosis),胞饮(pinocytosis)药物通过膜内陷小泡进入细胞 胞吐(exocytosis)药物通过胞裂外排由细胞内转运至细胞外 This mechanism is important for the transport of some macromolecules (e.g. insulin, which crosses the b
11、lood-brain barrier by this process), but not for small molecules.,二 药物在体内的存在形式,游离型(free) 结合型(bound) Transmembrane movement of drug generally is limited to unbound drug; thus drug-protein complexes constitute an inactive reservoir of drug that can influence both therapeutic as well as unwanted drug e
12、ffects.,第 二 节 药物的体内过程 Absorption, Distribution, Metabolism and Excretion,吸收,药物由给药部位进入全身血循环的过程 存在于除静脉给药方式外的所有其它给药途径 途径:oral, sub-lingual, injection, inhalation, rectal, intra-vaginal, intra-nasal. topical ? 吸收快慢次序:血管内吸入舌下直肠肌肉内皮下口服皮肤,口服,The oral route (PO) is usually preferred. Advantages The safest,
13、most convenient, and most economical Disadvantages Limited absorption of some drugs Irritation to the GI mucosa Destruction of some drugs by digestive enzymes or low gastric pH Irregularities in absorption or propulsion in the presence of food or other drugs The need for cooperation on the part of t
14、he patient First pass elimination. First pass metabolism of a drug can be avoided by sublingual administration and partially avoided by rectal administration.,小肠吸收,消化道吸收最主要部位 吸收面积大 血流量丰富,毛细血管壁通透性强 药物与之接触时间长 小肠既存在弱酸性环境,也存在弱碱性环境,胃肠道各部位吸收面积(m2) 口腔 0.5-l .0 直肠 0.02 胃 0.1-0.2 小肠 100 大肠 0.04-0.07,pH of Se
15、lective Body Fluids,血液循环示意图,首过消除(Presystemic/First-pass eliminaiton) 药物由用药部位到达全身血循环前被组织器官代谢损失掉一部分的现象,First pass metabolism of drugs may occur as they cross the intestine or transit the liver eg: nitroglycerin Other drugs may be destroyed before absorption eg: penicillin Such reactions decrease deliv
16、ery to the target tissues,静脉注射给药(Intravenous) 直接将药物注入血管 不存在“吸收”过程,无“首关消除” 肌肉注射和皮下注射 (Intramuscular and subcutaneous injection) 被动扩散过滤,吸收快而全 毛细血管壁孔半径40,大多水溶性药可滤过,注射给药特点,The administration of injection are technically more difficult and usually must be performed by a heath care professional. A. advant
17、ages include: (1) a faster onset (2) more reliable absorption (3) no first pass metabolism B. Disadvantages include: (1) more difficult administration. (2) pain or necrosis at the site of injection (3) possibility of infection (4) toxicity from a bolus intravenous injection (5) necessity of dissolvi
18、ng the drug if given intravenously.,呼吸道给药,通过喷雾或气雾给药方式 大颗粒粘附于呼吸道粘膜发挥局部作用 小分子由呼吸道粘膜或肺泡上皮细胞吸收 气体和挥发性药物直接进入肺泡,吸收迅速 肺泡表面积大(100-200m2) 血流量大(肺毛细血管面积80m2 ),舌下、直肠给药 局部给药 经皮给药:通过皮肤吸收产生局部或全身作用,药物吸收缓慢,作用持久 经粘膜 吸收快于皮肤 口腔、鼻、支气管、直肠、阴道 皮下缓释给药,影响药物吸收的因素,药物理化性质和剂型 首过消除 给药途径 甘露醇 ivgtt, po 硫酸镁 ivgtt, po 药物/食物相互作用 Envir
19、onmental pH Blood flow to the absorption site Total surface area available for absorption Contact time at the absorption surface Expression of P-glycoprotein,药物吸收定量参数,达峰时间(Tmax) 达峰浓度(Cmax) 曲线下面积(AUC) 生物利用度(F),2. 分布 (Distributation),药物从血循环到达全身各个组织的过程 规律: 先“分布”,然后“再分布” 分布部位存在选择性 在血液循环和器官组织中浓度可达动态平衡 前者
20、间接反映靶器官药物浓度 后者决定药物效应和毒性强弱 血药浓度预测疗效强弱,脂溶性 组织器官血流量 组织结合、分布的选择性 血浆蛋白结合率 体液pH和药物离解度 体内屏障,Factors modulating drug distribution:,血浆蛋白结合(Plasma protein binding),可逆性(Reversible equilibrium) 可饱和性(Saturable) DP(Non-permeable)不能透过细胞膜,不能产生药效 非特异性和竞争性 (Nonspecific & competitive),对血浆蛋白质结合有相互作用的药物,思考,血浆蛋白结合率高的药物药量
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